Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the elderly in this country. The sequelae of biochemical, cellular and/or molecular events leading to the pathogenesis of AMD are poorly understood, although it has been proposed that a threshold event occurs during normal aging that leads to AMD. Two abnormal extracellular deposits, drusen and basal laminar deposits (BLD), are significant risk factors for the development of both the atrophic and exudative forms of AMD. Despite this correlation, remarkably little is known about the molecular composition of these deposits and there in no general consensus concerning their origin. Furthermore, it is unclear if drusen and BLD are a cause or a consequence of RPE cell dysfunction that occurs in AMD. Preliminary studies conducted during the past two years have identified an array of DRAMs, many of which are common to other diseases - including amyloidosis, elastosis and atherosclerosis - that are characterized by the formation of extracellular deposits. The emphasis of this proposal is directed towards providing rigorous analyses of drusen and BLD composition and origin and on the identification of RNAs that may be differentially expressed by RPE cells associated with drusen and BLD. Hard and soft drusen will be enriched and molecular compositions determined immunochemically and biochemically. Definitive information pertaining to the relationship between BLD and basal laminae-associated molecules will be obtained and the relationship between BLD and choroidal collagenase activities will be assessed. In addition, the feasibility of generating an in vitro model for the generation of BLD will be tested. Finally, mRNAs that are expressed differentially in RPE and choroidal cells from drusen in BLD-rich eyes from aged/AMD donors as compared to age-matched donors without these deposits will be sought using mRNAs differential display. It is anticipated that the research proposed in this proposal will complement other clinical, genetic, pathological, and cellular investigations for an insight into the biology of, and ultimately a cure for, AMD.